Biaryl substituted 4-amino-butyric acid amides

ABSTRACT

The invention relates to biaryl substituted 4-amino-butyric acid derivatives of formula I ##STR1## wherein COX and COX&#39; independently represent carboxyl or carboxyl derivatized in form of a pharmaceutically acceptable ester or amide; R 1  represents hydrogen, lower alkyl, C 3  -C 7  -cycloalkyl-lower alkyl, aryl-lower alkyl, biaryl-lower alkyl, lower alkoxy, aryl-lower alkoxy, aryloxy, N-lower alkylamino, N,N-di-lower alkylamino, N-aryl-lower alkylamino, N,N-di-aryl-lower alkylamino, N-arylamino, N,N-diarylamino, lower alkanoylamino, aryl-lower alkanoylamino or aroylamino; R 2  represents hydrogen, hydroxy, lower alkoxy, lower alkyl, aryl-lower alkyl, C 3  -C 7  -cycloalkyl-lower alkyl, amino-lower alkyl, hydroxy-lower alkyl, lower alkylthio-lower alkyl, lower alkoxy-lower alkyl, aryl-lower alkylthio-lower alkyl or aryl-lower alkoxy-lower alkyl; biaryl represents phenyl substituted by carbocyclic or heterocyclic aryl; A represents a direct bond, lower alkylene, phenylene or cyclohexylene; m represents 1 or zero, provided that m represents 1 when A is a direct bond; or pharmaceutically acceptable salts thereof; pharmaceutical compositions comprising said compounds; methods for the preparation of said compounds and for the preparation of intermediates; and methods of treating disorders in mammals which are responsive to the inhibition of neutral endopeptidases by administration of said compounds to mammals in need of such treatment.

This is a continuation of Ser. No. 07/824,132, filed Jan. 22, 1992, nowU.S. Pat. No. 5,217,996.

SUMMARY OF THE INVENTION

Endogenous atrial natriuretic peptides (ANP), also called atrialnatriuretic favors (ANF) have diuretic, natriuretic and vasorelaxantfunctions in mammals. The natural ANF peptides are metabolicallyinactivated, in particular by a degrading enzyme which has beenrecognized to correspond to the enzyme neutral endopeptidase (NEP) EC3.4. 24.11, also responsible for e.g. the metabolic inactivation ofenkephalins.

The aim of the present invention is to provide novel biaryl substituted4-amino-butyric acid amide derivatives described below which arc usefulas neutral endopeptidase (NEP) inhibitors, e.g. as inhibitors of theANF-degrading enzyme in mammals, so as to prolong and potentate thediuretic, natriuretic and vasodilator properties of ANF in mammals, byinhibiting the degradation thereof to less active metabolites. Thecompounds of the invention arc thus particularly useful for thetreatment of conditions and disorders responsive to the inhibition ofneutral endopeptidase EC 3.4. 24.11, particularly cardiovasculardisorders, such as hypertension, renal insufficiency including edema andsalt retention, pulmonary edema and congestive heart failure. By virtueof their inhibition of neutral endopeptidase, the compounds of theinvention may also be useful for the treatment of pain, depression andcertain psychotic conditions. Other potential indications include thetreatment of angina, premenstrual syndrome, Meniere's disease,hyperaldosteronism, hypercalciuria, ascites, glaucoma, asthma,inflammations and gastrointestinal disorders such as diarrhea, irritablebowel syndrome and gastric hyperacidity.

The present invention relates to biaryl substituted 4-amino-butyric acidderivatives of formula I ##STR2## wherein COX and COX' independentlyrepresent carboxyl or carboxyl derivatized in form of a pharmaceuticallyacceptable ester or amide; R_(l) represents hydrogen, lower alkyl. C₃--C₇ -cycloalkyl-lower alkyl, aryl-lower alkyl, biaryl-lower -alkyl,lower alkoxy, aryl-lower alkoxy, aryloxy, N-lower alkylamino.N,N-di-lower alkylamino, N-aryl-lower alkylamino, N,N-di-aryl-loweralkylamino, N-arylamino, N,N-diarylamino, lower alkanoylamino,aryl-lower alkanoylamino or aroylamino; R₂ represents hydrogen, hydroxy,lower alkoxy, lower alkyl, aryl-lower alkyl, C₃ -C₇ -cycloalkyl-loweralkyl, amino-lower alkyl, hydroxy-lower alkyl, lower alkylthio-loweralkyl, lower alkoxy-lower alkyl, aryl-lower alkylthio-lower alkyl oraryl-lower alkoxy-lower alkyl; biaryl represents phenyl substituted bycarbocyclic or heterocyclic aryl; A represents a direct bond, loweralkylene, phenylene or cyclohexylene; m represents 1 or zero, providedthat m represents 1 when A is a direct bond; or a pharmaceuticallyacceptable salt thereof.

Pharmaceutically acceptable ester and amide derivatives are preferablyprodrug derivatives, such being convertible by solvolysis or underphysiological conditions to the free carboxylic acids of formula Iwherein COX and/or COX' represent carboxyl.

Compounds of formula I and derivatives thereof, depending on the natureof substituents, possess one or more asymmetric carbon atoms. Theresulting diastereoisomers and optical antipodes are encompassed by theinstant invention.

DETAILED DESCRIPTION OF THE INVENTION

The definitions used herein, unless denoted otherwise, have thefollowing meanings within the scope of the present invention.

The term biaryl represents phenyl substituted by carbocyclic aryl orheterocyclic aryl as defined herein, ortho, meta or para to the point ofattachment of the phenyl ring, advantageously para; biaryl is alsorepresented as the --C₆ H₄ --R₃ substituent in formulae herein.

Carbocyclic aryl preferably represents preferably monocyclic carbocyclicaryl or optionally substituted naphthyl.

Monocyclic carbocyclic aryl represents optionally substituted phenyl,being preferably phenyl or phenyl substituted by one to threesubstituents, such being advantageously lower alkyl, hydroxy, loweralkoxy, lower alkanoyloxy, halogen, cyano, trifluoromethyl, loweralkanoylamino or lower alkoxycarbonyl. Monocyclic carbocyclic arylparticularly preferably represents phenyl or phenyl substituted by loweralkyl, lower alkoxy, hydroxy, halogen, cyano or trifluoromethyl.

Optionally substituted naphthyl represents 1- or 2-naphthyl or 1- or2-naphthyl preferably substituted by lower alkyl, lower alkoxy orhalogen.

Heterocyclic aryl represents preferably monocyclic heterocyclic arylsuch as optionally substituted thienyl, indolyl, imidazolyl, furanyl,pyridyl, pyrrolyl or N-lower alkylpyrrolyl.

Optionally substituted furanyl represents 2- or 3-furanyl or 2- or3-furanyl preferably substituted by lower alkyl.

Optionally substituted pyridyl represents 2-, 3- or 4-pyridyl or 2-, 3-or 4-pyridyl preferably substituted by lower alkyl, halogen or cyano.

Optionally substituted thienyl represents 2- or 3-thienyl or 2- or3-thienyl preferably substituted by lower alkyl.

Optionally substituted indolyl represents preferably 2- or 3-indolyl or2- or 3-indolyl preferably substituted by lower alkyl, lower alkoxy orhalogen.

Optionally substituted imidazolyl is preferably 1- or 2-imidazolyl or 1-or 2-imidazolyl preferably substituted by lower alkyl.

Aryl as in aryl-lower alkyl, aryl-lower alkoxy, aryloxy, N-arylamino,N,N-diarylamino, aryl-lower alkoxycarbonyl or aryl-lower alkanoylaminois preferably phenyl or phenyl substituted by one or two of lower alkyl,lower alkoxy, hydroxy, lower alkanoyloxy, halogen, trifluoromethyl,cyano, lower alkanoylamino or lower alkoxycarbonyl.

The term "lower" referred to herein in connection with organic radicalsor compounds respectively defines such with up to and including 7,preferably up and including 4 and advantageously one or two carbonatoms. Such may be straight chain or branched.

A lower alkyl group preferably contains 1-4 carbon atoms and representse.g. ethyl, n- or iso-propyl, n-, iso-, sec.- or tert.-butyl oradvantageously methyl.

A lower alkoxy group preferably contains 1-4 carbon atoms and representsfor example methoxy, n-propoxy, isopropoxy, n-, iso-, sec.- ortert.-butoxy or advantageously ethoxy.

Aryl-lower alkyl is advantageously benzyl or phenethyl optionallysubstituted by one or two of lower alkyl, lower alkoxy, hydroxy, loweralkanoyloxy, halogen or trifluoromethyl.

Aryl-lower alkoxy represents advantageously e.g. benzyloxy, benzyloxysubstituted by lower alkyl, lower alkoxy, lower alkanoyloxy, halogen ortrifluoromethyl, or pyridylmethoxy.

Aryloxy preferably represents phenoxy or phenoxy substituted by loweralkyl, lower alkoxy, lower alkanoyloxy, halogen or trifluoromethyl.

N-arylamino and N,N-diarylamino represent advantageously N-phenylaminoor N,N-diphenylamino optionally substituted in the phenyl moieties orphenyl moieties by lower alkyl, lower alkoxy, hydroxy, loweralkanoyloxy, halogen or trifluoromethyl.

The term C₃ -C₇ -cycloalkyl represents a saturated cyclic hydrocarbonradical which contains 3 to 7 and preferably 5 to 7 ring carbons and is,most preferably, cyclopentyl or cyclohexyl.

The term cycloalkyl-lower alkyl represents preferably 1- or2-(cyclopentyl or cyclohexyl)ethyl, 1-, 2- or 3-(cyclopentyl orcyclohexyl)propyl, or 1-, 2-, 3- or 4-(cyclopentyl or cyclohexyl)-butyl.

Amino-lower alkyl represents preferably amino-(ethyl, propyl or butyl),particularly omega-amino-(ethyl, propyl or butyl).

A N-lower alkylamino group preferably contains 1-4 carbon atoms in thelower alkyl portion and represents, for example, N-n-propyl-amino.N-iso-propylamino, N-n-butylamino, N-tert.-butylamino and advantageouslyN-methylamino or N-ethylamino.

A N,N-di-lower alkylamino group preferably contains 1-4 carbon atoms ineach lower alkyl portion and represents, for example, N,N-dimethylamino,N-methyl-N -ethylamino and advantageously N,N-diethylamino.

Hydroxy-lower alkyl is for example 2-hydroxyethyl and preferablyhydroxymethyl.

Lower alkylthio as in lower alkylthio-lower alkyl representsadvantageously C₁ -C₄ -alkylthio and preferably methylthio or ethylthio.

Lower alkylene represents branched or straight chain alkylene of 1 to 7carbon atoms, advantageously straight chain (or linear) alkylene, suchas methylene, ethylene, propylene, butylene, pentylene or hexylene andmost preferably straight chain C₁ -C₄ -alkylene.

Phenylene represents preferably 1,3 or 1,4-phenylene, advantageously1,4-phenylene.

Cyclohexylene represents preferably 1,4-cyclohexylene.

Halogen (halo) preferably represents fluoro or chloro, but may also bebromo or iodo.

Lower alkanoyloxy advantageously contains 2 to 5 carbon atoms and ispreferably acetoxy, pivaloyloxy or propionyloxy.

Lower alkanoylamino advantageously contains 2 to 5 carbon atoms and ispreferably acetylamino or propionylamino.

A lower alkoxycarbonyl group preferably contains 1 to 4 carbon atoms inthe alkoxy portion and represents, for example, methoxycarbonyl,n-propoxycarbonyl, iso-propoxycarbonyl or advantageously ethoxycarbonyl.

Aroylamino is preferably benzoylamino or benzoylamino substituted on thebenzene ring by lower alkyl, lower alkoxy, halogen or trifluoromethyl.

Carboxyl esterified in form of a pharmaceutically acceptable ester,represents advantageously a prodrug ester that may be convertible bysolvolysis or under physiological conditions to the free carboxylicacid, such being preferably C₁ -C₂₀ -alkoxycarbonyl, advantageouslylower alkoxycarbonyl; (amino, acylamino, mono- or di-loweralkylamino)-lower alkoxycarbonyl; carboxy-lower alkoxycarbonyl, e.g.alpha-carboxy-lower alkoxycarbonyl; lower alkoxycarbonyl-loweralkoxycarbonyl, e.g. alpha-lower alkoxycarbonyl-lower alkoxycarbonyl;α-(di-lower alkylamino, amino, mono-lower alkylamino, morpholino,piperidino, pyrrolidino, 1-lower alkyl-piperazino)-carbonyl-loweralkoxycarbonyl; aryl-lower alkoxycarbonyl, preferably optionally (halo,lower alkyl or lower alkoxy)-substituted benzyloxycarbonyl, orpyridylmethoxycarbonyl; 1-(hydroxy, lower alkanoyloxy or loweralkoxy)-lower alkoxycarbonyl, e.g. pivaloyloxymethoxycarbonyl; (hydroxy,lower alkanoyloxy or lower alkoxy)-lower alkoxymethoxycarbonyl;bicycloalkoxycarbonyl-lower alkoxycarbonyl, e.g.bicyclo[2,2,1]-heptyloxycarbonyl-lower alkoxycarbonyl, especiallybicyclo-[2,2,1 ]-heptyloxycarbonylmethoxycarbonyl such asbornyloxycarbonylmethoxycarbonyl; 1-(lower alkoxycarbonyloxy)-loweralkoxycarbonyl; 5-indanyloxycarbonyl; 3-phthalidoxycarbonyl and (loweralkyl, lower alkoxy or halo)-substituted 3-phthalidoxycarbonyl;polyhydroxy-lower alkoxycarbonyl or protected polyhydroxy-loweralkoxycarbonyl in which polyhydroxy-lower alkoxy and protectedpolyhydroxy-lower alkoxy represent preferably dihydroxypropyloxy ortrihydroxybutyloxy wherein hydroxy groups are free or one or more, asappropriate, are protected in form of esters, e.g. a lower alkanoyl or abenzoyl ester, in form of ethers, e.g. a lower alkyl or benzyl ether,or, in case two vicinal hydroxy groups are involved, in the form ofacetals or ketals, e.g. a lower alkylidene, a benzylidene or a 5- or6-membered cycloalkylidene derivative.

Protected polyhydroxy-lower alkoxycarbonyl advantageously represents(2,2-dimethyl-1,3-dioxolan-4-yl)-methoxycarbonyl.

Acyl as in acyloxy or acylamino represents preferably lower alkanoyl,carbocyclic aryl-lower alkanoyl, aroyl, lower alkoxycarbonyl oraryl-lower alkoxycarbonyl, advantageously lower alkanoyl. Loweralkoxycarbonyl for acyl is preferably t-butoxycarbonyl (abbreviatedt-BOC). Aryl-lower alkoxycarbonyl for acyl is preferablybenzyloxycarbonyl (abbreviated CBZ).

Carboxy-lower alkoxycarbonyl represents advantageously e.g.1-carboxyethoxycarbonyl.

Lower alkoxycarbonyl-lower alkoxycarbonyl represents advantageously e.g.1-(ethoxycarbonyl)ethoxycarbonyl.

Amino-lower alkoxycarbonyl, mono-lower alkylamino-lower alkoxycarbonyl,di-(lower)alkylamino-lower alkoxycarbonyl advantageously represent e.g.aminoethoxycarbonyl, ethylaminoethoxycarbonyl,diethylaminoethoxycarbonyl.

Lower alkylidene is preferably isopropylidene.

Cycloalkylidene is preferably cyclohexylidene.

Carboxyl esterified in form of a pharmaceutically acceptable prodrugester represents most advantageously C₁ -C₄ -alkoxycarbonyl,phenyloxycarbonyl, benzyloxycarbonyl optionally substituted on phenyl bylower alkyl, lower alkoxy, halo or trifluoromethyl,pivaloyloxymethoxycarbonyl, 1-(C₂ -C₄ -alkanoyloxy)-ethoxycarbonyl,(2,2-dimethyl-1,3-dioxolan-4-yl)-methoxycarbonyl, 5-indanyloxycarbonyl,3-phthalidoxycarbonyl, bornyloxycarbonylmethoxycarbonyl, 1-(C₁ -C₄-alkoxycarbonyloxy)-ethoxycarbonyl or 3-pyridylmethoxycarbonyl.

Carboxyl derivatized in the form of a pharmaceutically acceptable amiderepresents preferably carbamoyl or N-substituted carbamoyl,advantageously [lower alkylamino, arylamino, di-lower alkylamino,morpholino, N-lower alkylpiperazino, pyrrolidino, piperidino,perhydroazepino, (amino or acylamino)-lower alkylamino or aryl-loweralkylamino]-carbonyl.

Pharmaceutically acceptable salts are either pharmaceutically acceptableacid addition salts for any basic compounds of the invention or saltsderived from pharmaceutically acceptable bases for any acidic compoundsof the invention.

Pharmaceutically acceptable salts of basic compounds of the inventionare acid addition salts, which are preferably such of therapeuticallyacceptable inorganic or organic acids, such as strong mineral acids, forexample hydrohalic, e.g. hydrochloric or hydro-bromic acid, sulfuric,phosphoric or nitric acid; aliphatic or aromatic carboxylic or sulfonicacids, e.g. formic, acetic, propionic, succinic, glycollic, lactic,malic, tartaric, gluconic, citric, maleic, fumaric, pyruvic,phenylacetic, benzoic, 4-aminobenzoic, anthranilic, 4-hydroxybenzoic,salicylic, 4-aminosalicylic, pamoic, nicotinic, methanesulfonic,ethanesulfonic, hydroxyethanesulfonic, 1,2-ethanedisulfonic acid,benzenesulfonic, p-toluenesulfonic, naphthalenesulfonic, sulfanilic,cyclohexylsulfamic acid, or ascorbic acid.

Pharmaceutically acceptable salts of the acidic compounds of theinvention, e.g. those having a free carboxyl group are salts formed withpharmaceutically acceptable bases, e.g. alkali metal salts (e.g. sodium,potassium salts), alkaline earth metal salts (e.g. magnesium, calciumsalts), ammonium salts, mono-, di- or tri-lower (alkyl orhydroxyalkyl)-ammonium salts (e.g. ethanolammonium, diethanolammonium,triethanolammonium, tromethamine salts).

The compounds of the invention, of formula I and derivatives thereof maycontain several asymmetric carbon atoms, depending on the nature of thesubstituents. Thus the compounds of the invention exist in the form ofgeometric isomers, racemates, diastereoisomers, pure enantiomers ormixtures thereof, all of which are within the scope of the invention.

For example, the compounds of formula I exist in isomeric forms, e.g.wherein the asymmetric carbon atom on the butyryl chain bearing theR_(l) and/or biarylmethyl groups may either exist in the S or Rconfiguration. The compounds of the invention, e.g. those of formula Ihaving said two asymmetric centers exist as two different racemicdiastereoisomeric forms which may be called erythro and threo dependingon the relative orientation of the R_(l) and biarylmethyl substituentsof the chain. Each of the two racemates consists of the optically activeenantiomers (or antipodes) having (S,S), (R,R), (R,S) or (S,R)configurations, respectively.

Preferred is the threo racemic form and particularly the enantiomericform depicted in formula I' ##STR3## wherein COX, COX', R_(l), R₂, A,biaryl and m have the meanings as defined herein above for compounds offormula I. The compounds of formulae Ia, Ib, Dc, Id, Ie and If givenbelow are present as well, preferably in the enantiomeric form depictedin formula I'.

Illustrative thereof, in the above compounds of formula I wherein R₁ islower alkyl, the carbon atom carrying said substituent is assigned the(R)-configuration; and the carbon atom carrying the biarylmethylsubstituent is assigned the (S)-configuration.

More particularly, the present invention is concerned with and has forits object the compounds of formula Ia ##STR4## wherein COOR and COOR'independently represent carboxyl or carboxyl derivatized in form of apharmaceutically acceptable ester, R₁ represents hydrogen, lower alkyl,lower alkoxy, N-lower alkylamino, lower alkanoylamino, aryl-lower alkyl,aryl-lower alkoxy, aryloxy, N-arylamino or aroylamino wherein aryl ineach case represents phenyl optionally substituted by lower alkyl, loweralkoxy, halogen, hydroxy, cyano, acyloxy or trifluoromethyl, or arylrepresents thienyl or furanyl optionally substituted by lower alkyl; R₂represents hydrogen, hydroxy, lower alkyl or aryl-lower alkyl whereinaryl independently has the meaning given above under R₁ ; R₃ representsphenyl, or phenyl substituted by lower alkyl, lower alkoxy, halogen,cyano, acyloxy or trifluoromethyl; or R₃ represents thienyl or furanyloptionally substituted by lower alkyl; A represents a direct bond, loweralkylene, 1,4-phenylene or 1,4-cyclohexylene; m represents 1 or zeroprovided that m represents 1 when A is a direct bond; or apharmaceutically acceptable salt thereof.

Advantageously, R₃ is located in the para position.

Particularly preferred embodiments of the invention as described aboverelate to:

a) compounds wherein R₃ is phenyl or phenyl substituted by lower alkyl,lower alkoxy, halogen, cyano, acyloxy or trifluoromethyl;

b) compounds wherein A is lower alkylene, m represents I or zero, and R₂represents hydrogen, lower alkyl, hydroxy or lower alkoxy.

c) compounds wherein R₁ represents hydrogen, lower alkyl, lower alkoxyor aryl-lower alkyl wherein aryl represents phenyl optionallysubstituted by one or two of lower alkyl, lower alkoxy, halogen,hydroxy, cyano, acyloxy or trifluoromethyl; most preferably compoundswherein R₁ represents lower alkoxy or lower alkyl.

A particular embodiment of the invention relates to compounds of formulaIb ##STR5## wherein COOR and COOR' independently represent carboxyl orcarboxyl derivatized in form of a pharmaceutically acceptable ester, R₁is hydrogen, lower alkyl, lower alkoxy or aryl-lower alkyl wherein arylrepresents phenyl optionally substituted by lower alkyl, lower alkoxy,halogen, hydroxy, cyano, acyloxy or trifluoromethyl; R₂ representshydrogen, hydroxy or lower alkoxy; R₄ and R₅ independently representhydrogen, lower alkyl, hydroxy, lower alkoxy, halogen, cyano ortrifluoromethyl; A represents lower alkylene; m represents 1 or zero; ora pharmaceutical acceptable salt thereof.

Particularly preferred are compounds of formula Ic ##STR6## wherein COORand COOR' independently represent carboxyl or carboxyl derivatized inform of a pharmaceutically acceptable ester, R₁ is lower alkyl or loweralkoxy; R₄ represents hydrogen, lower alkyl, lower alkoxy, halogen, ortrifluoromethyl; n represents an integer 1 through 6; or apharmaceutical acceptable salt thereof.

Preferred are compounds of formula Ic wherein COOR and COOR'independently represent carboxyl, C₁ -C₂₀ -alkoxycarbonyl, (carbocyclicor heterocyclic aryl)-lower alkoxycarbonyl, (di-lower alkylamino,N-lower alkylpiperazino, morpholino, pyrrolidino, piperidino orperhydrazepino)-C₂ to C₄ -alkoxycarbonyl, dihydroxypropyloxycarbonylprotected in form of a ketal, 5-indanyloxycarbonyl,3-phthalidoxycarbonyl, Bicycloalkoxycarbonyl-lower alkoxycarbonyl,α-(lower alkoxycarbonyl or di-lower alkylaminocarbonyl)-loweralkoxycarbonyl, 1-(lower alkoxycarbonyloxy)-lower alkoxycarbonyl or1-(lower alkanoyloxy)-lower alkoxycarbonyl; or a pharmaceuticallyacceptable salt thereof.

Particularly preferred are said compounds of formula Ic wherein COOR andCOOR' independently represent carboxyl, C₁ -C₄ -alkoxycarbonyl,3-pyridylmethoxycarbonyl, benzyloxycarbonyl optionally substituted onphenyl by lower alkyl, lower alkoxy, halo or trifluoromethyl,5-indanyloxycarbonyl, 1-(C₂ -C₅ -alkanoyloxy)-ethoxycarbonyl,3-phthalidoxycarbonyl, (2,2'-dimethyl-1,3-dioxolan-4-yl)-methoxycarbonyl, bornyloxycarbonylmethoxycarbonyl,1-(C₁ -C₄ -alkoxycarbonyloxy)-ethoxycarbonyl; or a pharmaceuticallyacceptable salt thereof.

A preferred embodiment of the invention relates to compounds of formulaId ##STR7## wherein R₁ is lower alkyl; n is an integer 1 through 4; or apharmaceutically acceptable mono- or di-ester derivative thereof inwhich one or two of the acidic hydroxy groups of the carboxyl functionalgroups are esterified in form of a mono- or di-pharmaceuticallyacceptable ester, or a pharmaceutically acceptable salt thereof; or anoptical antipode thereof.

Preferred are said compounds of formula Id wherein R₁ is methyl and n is2; and mono- or di-esters thereof.

As discussed before, the butyric acid compounds of e.g. formula Id existin two distinct diastereomeric forms which may be called erythro andthreo. Preferred are e.g. the compounds of formula Id as the threodiastereomer (racemate), more particularly as the enantiomeric formhaving the R-configuration at C-atom 2 and the S-configuration at C-atom4 and wherein the butyryl portion is as depicted in formula Id' ##STR8##wherein R₁ and n are as defined under formula Id; or a pharmaceuticalacceptable mono- or diester derivative thereof; or a pharmaceuticalacceptable salt thereof.

Particularly preferred are compounds of formula Ie ##STR9## wherein COORand COOR' independently represent carboxyl or carboxyl esterified inform of a pharmaceutical acceptable prodrug ester, or a pharmaceuticallyacceptable salt thereof.

Particularly preferred embodiments of the invention as described aboverelate to:

(a) compounds of the above formula Ie wherein R and R' independentlyrepresent hydrogen, C₁ -C₄ -alkyl, benzyl optionally substituted onphenyl by lower alkyl, lower alkoxy, halo or trifluoromethyl,pivaloyloxymethyl, 1-(C₂ -C₄ -alkanoyloxy)-ethyl.(2,2-dimethyl-1,3-dioxolan4-yl)-methyl, 5-indanyl, 3-phthalidyl,bornyloxycarbonylmethyl, 1-(C₁ -C₄ -alkoxycasbonyloxy)-ethyl or3-pyridylmethyl; or a pharmaceutically acceptable salt thereof;

(b) compounds of the above formula Ie wherein COOR' is carboxyl; andCOOR represents carboxyl or carboxyl derivatized in form of apharmaceutically acceptable ester; or a pharmaceutically acceptable saltthereof;

(c) compounds of the above formula Ie having the R-configuration atC-atom 2 and the S-configuration at C-atom 4;

(d) the compound according to the above formula Ie wherein COOR isethoxycarbonyl and COOR' is carboxyl, namely being4-[N-(3-carboxy-1-oxopropyl)amino]-4-(p-phenylphenylmethyl)-2-methylbutanoicacid ethyl ester, the (2R, 4S)antipode thereof or a pharmaceuticalacceptable salt thereof.

The novel compounds of the invention are pharmacologically potentneutral endopeptidase enzyme inhibitors which inhibit e.g. thedegradation of atrial natriuretic factors (ANF) in mammals. They thuspotentiate the diuretic and natriuretic effect of exogenous orendogenous ANF in mammals.

The compounds of the invention are thus particularly useful in mammalsas diuretic, natriuretic (saluretic) and antihypertensive agents for thetreatment of e.g. hypertension, congestive heart failure and edema.

As neutral endopeptidase inhibitors, the compounds are also e.g.enkephalinase inhibitors so as to inhibit the degradation of endogenousenkephalins and may thus also be useful for the treatment of pain inmammals.

The above-cited properties are demonstrable in vitro and in vivo tests,using advantageously mammals, e.g. mice, rats, dogs, monkeys or isolatedorgans, tissues and preparations thereof. Said compounds can be appliedin vitro in the form of solutions, e.g. preferably aqueous solutions,and in vivo either enterally, parenterally, advantageouslyintravenously, e.g. as a suspension or in aqueous solution. The dosagein vitro may range between about 10⁻⁴ molar and 10⁻⁹ molarconcentrations. The dosage in vivo may range depending on the route ofadministration, between about 0.01 and 50 mg/kg, advantageously betweenabout 1.0 and 25 mg/kg.

The analgesic activity can be determined by measuring the potentiationof the analgesic effects of enkephalin and derivatives thereof, and byclassical analgesic tests, such as the phenyl-p-benzoquinone inducedwriting test [J. Pharmacol. Exp. Therap. 125, 237 (1959)] and the hotplate test in the mouse [J. Pharmacol. Exp. Therap. 107,385 (1953).

The antihypertensive activity can be determined in the spontaneouslyhypertensive rat, Goldblatt rat or Goldblatt dog by direct measurementof blood pressure. Advantageously, the effect is measured in theDOCA-salt hypertensive rat and/or renal hypertensive rat or dog model.

The diuretic (saluretic) activity can be determined in standard diureticscreens, e.g. as described in "New Antihypertensive Drugs", SpectrumPublications, 1976, pages 307-321, or by measuring the potentiation ofatrial natriuretic factor-induced natriuresis and diuresis in the rat.

The potentiation of ANF can also be determined by measuring the increasein ANF plasma level achieved.

The in vitro inhibition of neutral endopeptidase (NEP) 3.4.24.11 can bedetermined as follows:

Neutral endopeptidase 3.4.24.11 activity is determined by the hydrolysisof the substrate glutaryl-Ala-Ala-Phe-2-naphthylamide (GAAP) using amodified procedure of Orlowski and Wilk (1981). The incubation mixture(total volume 125 μl) contains 4.2 μg of protein (rat kidney cortexmembranes prepared by method of Maeda ct al, 1983), 50 mM tris buffer,pH 7.4 at 25° C., 500 μM substrate (final concentration), and leucineaminopeptidase M (2.5 μg). The mixture is incubated for 10 minutes at25° C. and 100 μl of fast garnet (250 μg fast garnet/ml of 10% Tween 20in 1M sodium acetate, pH 4.2) is added. Enzyme activity is measuredspectrophotometrically at 540 nm. One unit of NEP 24.11 activity isdefined as 1 nmol of 2-naphthylamine released per minute at 25° C. at pH7.4. IC.₅₀ values are determined, i.e. the concentration of testcompound required for 50% inhibition of the release of 2-naphthylamine.

Neutral endopeptidase activity is also determined using ANF as asubstrate. Atrial natriuretic factor degrading activity is determined bymeasuring the disappearance of rat-ANF (r-ANF) using a 3 minute reversephase-HPLC separation. An aliquot of the enzyme in 50 mM Tris HClbuffer, pH 7.4, is preincubated at 37° C. for 2 minutes and the reactionis initiated by the addition of 4 nmol of r-ANF in a total volume of 50μl. The reaction is terminated after 4 minutes with the addition of 30μl of 0.27% trifluoroacetic acid (TFA). Forty microliters of the mixtureis injected into a reverse phase-HPLC and analyzed using a C4 cartridgein a 3 minute, isocratic separation. Twenty-three percent of buffer B(0.1% TFA in 80% acetonitrile) is used. Buffer A is0.1% TFA in water.One unit of activity is defined as the hydrolysis of 1 nmol of r-ANF perminute at 37° C. at pH 7.4. IC₅₀ values are determined, i.e. theconcentration of test compound required for 50% inhibition of thehydrolysis of ANF.

The test compound is dissolved in dimethyl sulfoxide or 0.25M sodiumbicarbonate solution, and the solution is diluted with pH 7.4 buffer tothe desired concentration.

In vitro testing is most appropriate for the free carboxylic acids ofthe invention.

The effect of the compounds of the invention on rat plasma ANFconcentration can be determined as follows:

Male Sprague-Dawley rats (275-390 g) are anesthetized -with ketamine(150 mg/kg)/acepromazine (10%) and instrumented with catheters in thefemoral artery and vein to obtain blood samples and infuse ANF.respectively. The rats are tethered with a swivel system and are allowedto recover for 24 hours before being studied in the conscious,unrestrained state.

In this assay, plasma ANF levels are determined in the presence andabsence of NEP inhibition. On the day of study, all rats are infusedcontinuously with ANF at 450 ng/kg/min. i.v. for the entire 5 hours ofthe experiment. Sixty minutes after beginning the infusion, bloodsamples for baseline ANF measurements are obtained (time 0) and the ratsare then randomly divided into groups treated with the test compound orvehicle. Additional blood samples are taken 30, 60, 120, 180 and 240minutes after administration of the test compound.

Plasma concentrations are determined by a specific radioimmunoassay. Theplasma is diluted (X 12.5, X 25 and X 50) in buffer containing: 50 mMTris (pH 6.8), 154 mM NaCl, 0.3% bovine serum albumin, 0.01% EDTA. Onehundred microliters of standards [rANF (99-126)] or samples are added to100 μl of rabbit anti-rANF serum and incubated at 4° C. for 16 hours.Ten thousand cpm of [¹²⁵ I]rANF are then added to the reaction mixturewhich is incubated at 4° C. for an additional 24 hours. Goat anti-rabbitIgG serum coupled to paramagnetic particles is added to the reactionmixture and bound [¹²⁵ I]rANF is pelleted by exposing the mixture to anattracting magnetic rack. The supernatant is decanted and the pelletscounted in a gamma counter. All determinations are performed induplicate. Plasma ANF levels are expressed as a percent of thosemeasured in vehicle-treated animals which received ANF alone (450ng/kg/min i.v.).

Illustrative of the invention,N-(3-carboxy-1-oxopropyl)-(4S)-(p-phenylphenylmethyl)-4-amino-2R-methylbutanoicacid ethyl ester at doses of about 1-30 mg/kg p.o., administered in 10%ethanol/polyethylene glycol (PEG) 400, produces significant increases inplasma ANF levels.

The antihypertensive effect can be determined in desoxycorticosteroneacetate (DOCA)-salt hypertensive rats.

DOCA-salt hypertensive rats (280-380 g) are prepared by the standardmethod. Rats underwent a unilateral nephrectomy and one week later areimplanted with silastic pellets containing 100 mg/kg of DOCA. The ratsare maintained on 1% NaCl/0.2% KCl drinking water for three to fiveweeks until sustained hypertension is established. The antihypertensiveactivity is evaluated at this time.

Two days before an experiment, the rats are anesthetized withmethoxyflurane and instrumented with catheters in the femoral artery tomeasure arterial blood pressure. Forty-eight hours later, baselinearterial pressure and heart rate are recorded during a 1 hour period.The test compound (30 mg/kg p.o.) or vehicle is then administered andthe same cardiovascular parameters are monitored for an additional 5hours.

Illustrative of the invention,N-(3-carboxy-1-oxopropyl)-(4S)-(p-phenylphenylmethyl)4-amino-2R-methylbutanoicacid ethyl ester at a dose of 30 mg/kg p.o., administered in PEG 400,produces a significant reduction in blood pressure in the DOCA-salthypertensive rat model.

The potentiation of the natriuretic effect of ANF can be determined asfollows:

Male Sprague-Dawley rats (280-360 g) are anesthetized with Inactin (100mg/kg i.p.) and instrumented with catheters in the femoral artery,femoral vein and urinary bladder to measure arterial pressure,administer ANF and collect urine, respectively. A continuous infusion ofnormal saline (33 μl/min) is maintained throughout the experiment topromote diuresis and sodium excretion. The experimental protocolconsists of an initial 15 minute collection period (designated aspre-control) followed by three additional collection periods.Immediately after completion of the pre-control period, test compound orvehicle is administered; nothing is done for the next 45 minutes. Then,blood pressure and renal measurements are obtained during a secondcollection period (designated control; 15 min). At the conclusion ofthis period, ANF is administered (1 μg/kg i.v. bolus) to all animals andarterial pressure and renal parameters are determined during twoconsecutive 15 minutes collection periods.

Mean arterial pressure, urine flow and urinary sodium excretion aredetermined for all collection periods. Blood pressure is measured with aGould p50 pressure transducer, urine flow is determined gravimetrically,sodium concentration is measured by flame photometry, and urinary sodiumexcretion is calculated as the product of urine flow and urine sodiumconcentration.

The compounds of the invention are thus particularly useful asinhibitors of neutral endopeptidase, enhancing the potency and durationof action of atrial natriuretic peptide(s). The compounds are thereforeparticularly useful for the treatment of cardiovascular disorders suchas hypertension, edema and salt retention, and cardiac conditions suchas congestive heart failure.

The compounds of the invention of formula I may be prepared using thefollowing process which comprises: condensing a compound of formula II##STR10## wherein COX, R₁ and biaryl have the meaning as defined above,in temporarily protected form if required; with a compound of formulaIII ##STR11## or a reactive functional derivative thereof, wherein A,R₂, m and COX' have the meaning as defined above, in temporarilyprotected form if required; and, if temporarily protecting anyinterfering reactive group(s), removing said protecting group(s), andthen isolating the resulting inventive compound; and, if desired,converting any resulting compound into another compound of theinvention, and/or, if desired, converting a resulting free compound intoa salt or a resulting salt into the free compound or into another salt,and/or, if desired, separating a mixture of isomers or racematesobtained into the single isomers or racemates, and/or, id desired,resolving a racemate obtained into the optical antipodes.

In starting compounds and intermediates which are convened to thecompounds of the invention in a manner described herein, functionalgroups present, such as carboxyl, amino and hydroxy groups, areoptionally protected by conventional protecting groups that are commonin preparative organic chemistry. Protected carboxyl, amino and hydroxygroups are those that can be convened under mild conditions into freecarboxyl, amino and hydroxy groups without other undesired sidereactions taking place.

The purpose of introducing protecting groups is to protect thefunctional groups from undesired reactions with reaction components andunder the conditions used for carrying out a desired chemicaltransformation. The need and choice of protecting groups for aparticular reaction is known to those skilled in the art and depends onthe nature of the functional group to be protected (carboxyl group,amino group etc.), the structure and stability of the molecule of whichthe substituent is a pan, and the reaction conditions.

Well-known protecting groups that meet these conditions and theirintroduction and removal are described, for example, in J. F. W. McOmie,"Protective Groups in Organic Chemistry", Plenum Press, London, New York1973, T. W. Greene, "Protective Groups in Organic Synthesis", Wiley, NewYork 1984, and also in "The Peptides", Vol. I, Schroeder and Luebke,Academic Press, London, New York, 1965.

The preparation of compounds of the invention according to the aboveprocess, i.e. the condensation of an amine of formula II with the acidof formula 1II, or a functional reactive derivative thereof, is carriedout by methodology well-known for peptide synthesis.

Reactive functional derivatives of compounds of formula III arepreferably halides, anhydrides such as succinic anhydride, glutaricanhydride, or mixed anhydrides such as the pivaloyl, alkoxycarbonyl orcyanoacetyl anhydride.

The condensation of an amine of formula II with a free carboxylic acidof formula III is carried out advantageously in the presence of acondensing agent such as dicyclohexylcarbodiimide orN-(3-dimethylaminopropyl)-N'-ethylcarbodiimide and hydroxybenzotriazolein an inert polar solvent such as dimethylformamide or methylenechloride, preferably at room temperature.

The condensation of an amine of formula II with a reactive functionalderivative of an acid of formula III in the form of an acid halide,advantageously an acid chloride, anhydride or mixed anhydride, iscarried out in an inert solvent such as toluene or methylene chloride,advantageously in the presence of a base, e.g. an inorganic base such aspotassium carbonate or an organic base such as triethylamine orpyridine, preferably at room temperature.

The starting materials of formula III are acids or functionalderivatives thereof known in the art or which may be prepared byconventional methods known in the art.

The starting materials of formula II are known or, if new, may beprepared according to conventional methods, e.g., those illustrated bythe examples herein.

For example, the compounds of formula II may be prepared by converting acompound of formula IV ##STR12## wherein COX, R₁ and biaryl have themeaning mentioned above, in temporarily protected form if required, intoa suitable carboxylic acid amide or carboxylic acid azide and thensubjecting this compound to a Hofmann reaction or to a Curtiusrearrangement in a manner well known in the art. The compounds offormula IV are known, for example, from U.S. Pat. No. 5,021,430 or maybe prepared analogous to the methods described therein.

In a preferred alternative route, the starting materials of formula IImay be prepared by

(a) reducing the carboxylic group of a biarylalanine of formula V##STR13## in temporarily protected form if required, to yield therespective aldehyde;

(b) subsequently reacting said aldehyde with a triphenylphosphoniumcompound of formula VI ##STR14##

(c) hydrogenating the resulting compound of formula VII ##STR15## and,if temporarily protecting any interfering reactive group(s), removingsaid protective group(s) and then isolating the resulting product. Inthe above formulae V, VI and VII, the variables COX, R₁ and biaryl havethe meaning as defined under formula I. The above reaction steps (a),(b) and (c) are carried out by methodology well-known in the an.

For example, in step (a) the compound of formula V, advantageously anamino protected compound of formula V, is reacted first of all with ahydroxylamine or a salt thereof, e.g. with N,O-dimethylhydroxylaminehydrochloride; the resulting hydroxylmine amide is then reduced to thealdehyde in a conventionel manner, e.g. with lithium aluminum hydride.

Reaction step (b) represents a conventional Wittig reaction which may beperformed in a manner known in the art.

Reaction step (c) as well represents a commonly known hydrogenationreaction which may be performed e.g. with molecular hydrogen in thepresence of a suitable, catalyst such as palladium/charcoal.

Biarylalanines of formula V are either known in the art or can beprepared according to methods reported in the art.

As to the preparation of the biarylalanines of formula V as startingmaterials in optically active form, such can be prepared e.g. byresolution or by one of the following methods:

(a) Adapting a method described in Tetrahedron Letters 1988, 6075, abiarylmethanol, e.g. 4-biphenylylmethanol, is convened to a reactivederivative, e.g. the bromide, which is then condensed with an N-acylderivative of 2,3-diphenyl-6-oxomorpholine, e.g. theN-carbobenzyloxy-(2R,3S)-isomer, in the presence of a strong base suchas sodium bis-trimethylsilylamide, to yield e.g. N-carbobenzyloxy-2(R),3(S), 5(S)-6-oxo-2,3-diphenyl-5-(4-biphenylylmethyl)morpholine.Catalytic hydrogenolysis, e.g. using hydrogen and palladium on charcoalas catalyst, yields the optically active (S)-(+)-4-biphenylalanine.

(b) Alternatively, using the Pd (0)-catalyzed cross-coupling reactiondescribed in Tetrahedron Letters 31, 1665 (1990), J. Organic Chemistry55, 906 (1990) and Tetrahedron 45, 6670 (1989) as developed by W. Shiehet al, the substantially optically pure chiral biarylalanines, of theformula ##STR16## or the N-acyl and/or carboxy ester derivatives thereofwherein R₃ has meaning as defined hereinabove, can be prepared by:condensing a reactive esterified optically active tyrosine derivative ofthe formula ##STR17## wherein the amino and carboxy groups are inprotected form (as N-acyl and esterified carboxy ester derivatives), andZ represents reactive esterified hydroxy (advantageouslytrifluoromethylsulfonyloxy) with an aryl boronic acid in which arylcorresponds to R₃ as defined above, in the presence of a palladium (0)catalyst, in particular tetrakis(triphenylphosphine)palladium (0), andin the presence of an anhydrous base (such as an alkali metalcarbonate), in an inert solvent (such as xylene or toluene) at anelevated temperature ranging from about 50° to 150° C., and removing anyprotecting groups as required.

For example, N-t-butoxycasbonyl-tyrosine methyl ester is first convertedto N-t-butoxycarbonyl-4-trifluoromethylsulfonyloxy-phenylalanine methylester (N-t-butoxycarbonyltyrosine triflate methyl ester). This compoundis then condensed with an arylboronic acid (e.g. phenylboronic acid) inthe presence of anhydrous potassium carbonate, and tetrakis(triphenylphosphine) palladium (0) complex as catalyst, in toluenepreferably at an elevated temperature, advantageously at about 100° toobtain N-t-butoxycarbonyl-4-biphenylalanine methyl ester. AfterN-deacylation, substantially optically pure 4-biphenylalanine methylester is obtained with a configuration corresponding to that of thetyrosine derivative used as starting material.

The arylboronic acids are either commercial or can be prepared asdescribed in the literature, e.g. J. Org. Chem. 49, 5237 (1984).

The triphenylphosphonium compounds of formula VI are either known in theart or can be prepared according to methods reported in the art.

Compounds of the invention wherein COX or COX' represent carboxylderivatized in form of a pharmaceutically acceptable amide can also beprepared according to the above methods using corresponding startingmaterials wherein COX or COX' represent carbamoyl or N-substitutedcarbamoyl.

The compounds of the invention so obtained, can be convened into eachother according to conventional methods. Thus, for example, resultingamides or esters may be hydrolyzed with aqueous alkalies, such as alkalimetal carbonates or hydroxides. Resulting free acids may be esterifiedwith e.g. said unsubstituted or substituted alkanols or reactiveesterified derivatives thereof such as alkyl halides, or diazoalkanes.Free acids are also converted into said metal, ammonium or acid additionsalts in conventional manner.

Thus, any resulting free acid or base can be converted into acorresponding metal, ammonium or acid addition salt respectively, byreacting it with an equivalent amount of the corresponding base, basicsalt, acid or ion exchange preparation, e.g. said free acids with alkalior ammonium hydroxides or carbonates, or e.g. free amines with saidinorganic or organic acids respectively. Any resulting salt may also beconverted into the free compound, by liberating the latter with strongeracids or bases, respectively. In view of the close relationship betweenthe free compounds and the salts thereof, whenever a compound of theinvention, or intermediate, is referred to in this context, acorresponding salt is also intended, provided such is possible orappropriate under the circumstances.

The compounds, including their salts, may also be obtained in the formof their hydrates, or include other solvents used for thecrystallization. Furthermore, the functional derivatives of the freeacids of formula I, wherein the carboxy groups are esterified byidentical or different radicals may be prepared by condensing a freeacid of formula I or a mono- or all-ester derivative thereof with anesterifying agent of the formula VIII

    R.sub.6 --Z                                                (VIII)

wherein Z represents hydroxy or a reactive esterified hydroxyl group;and R₆ represents an esterifying radical as defined herein for thecarboxylic esters (encompassed e.g. by COX or COX' representingesterified carboxy), in particular said non-aromatic radicals.

A reactive esterified hydroxyl group, such as Z in a compound of theformula VIII, is a hydroxyl group esterified by a strong inorganic ororganic acid. Corresponding Z groups are in particular halo, for examplechloro, bromo or preferably iodo, also sulfonyloxy groups, such as loweralkyl- or arylsulfonyloxy groups, for example (methane-, ethane-,benzene- or toluene-) sulfonyloxy groups, also thetrifluoromethylsulfonyloxy group.

The esterification of the carboxyl groups, optionally in salt form, witha compound of formula VIII wherein Z represents a reactive esterifiedhydroxyl group, is performed in a manner known per se, in the presenceof for example an organic base, such as an organic amine, for example atertiary amine, such as tri-lower alkylamine, for exampletrimethylamine, triethylamine or ethyl-di-isopropylamine, anN,N-di-lower-alkyl-aniline, for example N,N-di-methylaniline, a cyclictertiary amine, such as an N-lower-alkylated morpholine, for exampleN-methyl-morpholine, a base of the pyridine type, for example pyridine,an inorganic base, for example hydroxides, carbonates, or hydrogencarbonates of alkali metals or alkaline-earth metals, for examplesodium, potassium or calcium hydroxide, carbonate or hydrogen carbonate,or a quaternary ammonium base, such as a tetraalkylammonium hydroxide,carbonate or hydrogen carbonate, for example in which alkyl is e.g.methyl, ethyl, propyl, isopropyl, butyl, or the like, or an alkali metalsalt of bis-trialkylsilylamide (e.g. trimethyl) optionally in thepresence of a crown ether such as 18-crown-6 in a suitable inert solventor solvent mixture, e.g. acetonitrile, toluene, and the like.

A trifunctional free acid, e.g. of the formula I, or a monoester ordiester thereof, is preferably first convened into a salt of one of thestated organic or inorganic bases, especially into the sodium orpotassium salt, and is then reacted with a compound of the formula VIII.The compounds of formula VIII are known or can be prepared by methodswell-known to the art.

A compound of the formula or VIII wherein Z is a reactive esterifiedhydroxyl group can be prepared in situ. For example, a compound of theformula VIII wherein Z is chloro can be convened by treatment withsodium iodide in a solvent, for example in acetone or acetonitrile, intoa compound of the formula VIII wherein Z is iodo; or esterification canbe carded out with a chloro compound of the formula VIII in the presenceof sodium iodide.

Esterification of a compound with a free carboxyl group using in excessan alcohol of formula VIII (wherein Z represents hydroxy) is carried outin a manner known per se, e.g. in the presence of an acid catalyst e.g.sulfuric acid or boron trifluoride etherate, preferably at an elevatedtemperature, advantageously ranging from about 40° C. to 100° C.Alternately, the esterification of a compound with a free carboxyl groupcan be carried out with at least an equimolar mount of the alcohol inthe presence of a condensing agent such as dicyclohexylcarbodiimide orN-(3-dimethylaminopropyl)-N'-ethylcarbodiimide in a polar solvent suchas methylene chloride, in the presence of a base if required, e.g. suchas 4-(dimethylamino)pyridine.

Conversely, carboxylic acid esters can be convened to compounds of theinvention with a free carboxy group using methods and conditionsgenerally known in the an and illustrated herein. Depending on type ofester involved, useful reagents include aqueous acids or bases; alsoanhydrous reagents such as trialkylsilyl halides, hydrobromic acid inglacial acetic acid; also hydrogen and a hydrogenolysis catalyst Forinstance. trialkyl esters can be convened to the free trifunctionalacids by treatment with hydrobromic acid in glacial acetic acid, e.g. atroom temperature or elevated temperature. Also trialkyl esters can beconvened to the mono esters wherein carboxy only remains esterified, bytreatment with e.g. trimethylsilyl bromide at room temperature.

Any benzyl esters can be selectively hydrogenolyzed with e.g. hydrogenin the presence of a catalyst such as palladium on charcoal.

In the case mixtures of stereoisomers or optical isomers of the abovecompounds are obtained, these can be separated into the single isomersby methods in themselves known, e.g., by fractional distillation,crystallization and/or chromatography. Racemic products can be resolvedinto the optical antipodes, for example, by separation of diastereomericsalts thereof, e.g., for basic compounds by the fractionalcrystallization of d- or 1-(tartrate, mandelate or camphorsulfonate)salts, or for acidic compounds by fractional crystallization of d- or1-(alpha-methylbenzylamine, cinchonidine, cinchonine, quinine,quinidine, ephedrine, dehydroabietylamine, brucine or strychnine)-salts.

The above-mentioned reactions are carried out according to standardmethods, in the presence or absence of diluents, preferably such as areinert to the reagents and are solvents thereof, of catalysts, alkalineor acidic condensing or said other agents respectively and/or inertatmospheres, at low temperatures, room temperature or elevatedtemperatures, preferably near the boiling point of the solvents used, atatmospheric or superatmospheric pressure.

The invention further includes any variant of said processes, in whichan intermediate product obtainable at any stage of the process is usedas a starting material and any remaining steps are carried out, or theprocess is discontinued at any stage thereof, or in which the startingmaterials are formed under the reaction conditions, or in which thereaction components are used in the form of their salts or opticallypure antipodes. Mainly those starting materials should be used in saidreactions, that lead to the formation of those compounds indicated aboveas being preferred.

The present invention additionally relates to the use in mammals of thecompounds of the invention and their pharmaceutically acceptable,non-toxic acid addition salts, or pharmaceutical compositions thereof,as medicaments, e.g. as neutral endopeptidase inhibitors, e.g. for thetreatment of cardiovascular disorders such as hypertension, edema, saltretention and congestive heart failure.

The present invention also relates to the use of the compounds of theinvention for the preparation of pharmaceutical compositions especiallypharmaceutical compositions having neutral endopeptidase inhibitingactivity, and e.g. antihypertensive or saluretic activity.

The pharmaceutical compositions according to the invention are thosesuitable for enteral, such as oral or rectal, transdermal and parenteraladministration to mammals, including man, for the treatment ofcardiovascular disorders, such as hypertension, comprising an effectiveamount of a pharmacologically active compound of the invention or apharmaceutically acceptable salt thereof, alone or in combination withone or more pharmaceutically acceptable carriers.

The pharmacologically active compounds of the invention are useful inthe manufacture of pharmaceutical compositions comprising an effectiveamount thereof in conjunction or admixture with excipients or carrierssuitable for either enteral or parenteral application. Preferred aretablets and gelatin capsules comprising the active ingredient togetherwith a) diluents, e.g. lactose, dextrose, sucrose, mannitol, sorbitol,cellulose and/or glycine; b) lubricants, e.g. silica, talcum, stearicacid, its magnesium or calcium salts and/or polyethyleneglycol; fortablets also c) binders, e.g. magnesium aluminum silicate, starch paste,gelatin, tragacanth, methylcellulose, sodium carboxymethylcelluloseand/or polyvinylpyrrolidone; if desired) disintegrants, e.g. starches,agar, alginic acid or its sodium salt, or effervescent mixes; and/or e)absorbents, colorants, flavors and sweeteners. Injectable compositionsare preferably aqueous isotonic solutions or suspensions, andsuppositories are advantageously prepared from fatty emulsions orsuspensions. Said compositions may be sterilized and/or containadjuvants, such as preserving, stabilizing, wetting or emulsifyingagents, solution promoters, salts for regulating the osmotic pressureand/or buffers. In addition, the compositions may also contain othertherapeutically valuable substances. Said compositions are preparedaccording to conventional mixing, granulating or coating methods,respectively, and contain about 0.1 to 75%, preferably about 1 to 50 %,of the active ingredient.

Suitable formulations for transdermal application include an effectivemount of a compound of the invention with carrier. Advantageous carriersinclude absorbable pharmacologically acceptable solvents to assistpassage through the skin of the host. Characteristically, transdermaldevices are in the form of a bandage comprising a backing member, areservoir containing the compound, optionally with carriers, optionallya rate controlling barrier to deliver the compound to the skin of thehost at a controlled and predetermined rate over a prolonged period oftime, and means to secure the device to the skin.

A unit dosage for a mammal of about 50 to 70 kg may contain betweenabout 10 and 100 mg of the active ingredient. The dosage of activecompound is dependent on the species of warm-blooded animal (mammal),the body weight, age and individual condition, and on the form ofadministration.

The following examples are intended to illustrate the invention and arenot to be construed as being limitations thereon. Temperatures are givenin degrees Centigrade. If not mentioned otherwise, all evaporations areperformed under reduced pressure, preferably between about 15 and 100 mmHg. Optical rotations are measured at room temperature at 589 nm (D lineof sodium), 365 nm or other wavelengths as specified in the examples.

The prefixes R and S are used to indicate the absolute configuration ateach asymmetric center.

EXAMPLE 1

To a solution ofN-(3-carbo(t)butoxy-1-oxopropyl)-(4S)-(p-phenylphenylmethyl)-4-amino-2R-methylbutanoicacid ethyl ester (0.80 g) in 15 ml of CH₂ Cl₂ at room temperature areadded 3 ml of trifluoroacetic acid. The mixture is stirred overnight andconcentrated. The residue is dissolved in tetrahydrofuran (THF), and 6.5ml of 1N NaOH is added. The mixture is concentrated and triturated withether. The solid can be recrystallized from methylene chloride-hexane togive sodiumN-(3-carboxy-1-oxopropyl)-4S)-(p-phenylphenylmethyl)-4-amino-2R-methylbutanoic acid ethyl ester melting at 159°-160° C.; [α]_(D) ²⁰ =-11.4°(methanol).

The starting material is prepared as follows:

A solution of α-t-BOC-(R)-tyrosine methyl ester (5.9 g, 20 mmol) andpyridine (8 mL, 100 mmol) in methylene chloride (30 mL) is cooled to0°-5° C. Trifluoromethanesulfonic anhydride (4 mL, 23 mmol)is added at0°-5° C., and the resulting mixture is held for another 30 minutes. Thereaction mixture is diluted with water (60 mL) and methylene chloride(100 mL), and washed sequentially with 0.5N sodium hydroxide solution(1×50 mL), water (1×60 mL), 10% citric acid solution (2×75 mL) and water(1×60 mL). The organic phase is dried over MgSO₄ and concentrated to anoil. The oil is purified by column chromatography (silica gel,hexane/ethyl acetate, 2:1 to givemethyl(R)-2-(t-butoxycarbonylamino)-3-[4-(trifluoromethylsulfonyloxy)phenyl]-propionatewhich crystallizes on standing; m.p. 46°-48° C.; [α]²⁰ _(D) -36.01°(c=1,CHCl₃).

Nitrogen is passed through a suspension of(R)-2-(t-butoxycarbonyl-amino)-3-[4-(trifluoromethylsulfonyloxy)-phenyl]-propionate(1.75mmol), phenylboronic acid (3.5 mmol), anhydrous potassium carbonate(2.63 mmol) and toluene (17 mL) for 15 minutes.Tetrakis(triphenylphosphine)palladium(0) is added, and the mixture isheated at 85°-90° for 3 hours. The reaction mixture is cooled to 25° C.,diluted with ethyl acetate (17 mL) and washed sequentially withsaturated sodium bicarbonate (1×20 mL), water (1×20 mL), 10% citric acid(1×20 mL), water (1×20 mL) and saturated sodium chloride solution (1×20mL). The organic phase is concentrated, and the residue is purified bycolumn chromatography (silica gel, hexane/ethyl acetate 2:1) to yieldmethyl (R)-2-(t-butoxycarbonylamino)-3-(p-phenylphenyl)-propionate whichcan also be called N-(R)-t-butoxycarbonyl-(p-phenylphenyl)-alaninemethyl ester.

To a solution of N-(R)-t-butoxycarbonyl-(p-phenylphenyl)-alanine methylester (6.8 g) in 60 ml of THF and 20 ml of methanol are added 20 ml ofaqueous 1N sodium hydroxide solution. The mixture is stirred for 1 h atroom temperature and then acidified with 21 ml of 1N hydrochloric acid.The aqueous solution is extracted 3x with ethyl acetate. The combinedorganic extracts are dried (MgSO₄), filtered and concentrated to giveN-(R)-t-butoxycarbonyl-(p-phenylphenyl)-alanine, m.p. 98°-99° C., [α]²⁰_(D) -18.59° (c=1, methanol).

To a solution of N-(R)-t-butoxycarbonyl-(p-phenylphenyl)-alanine (4.8 g)in 70 ml of methylene chloride (CH₂ Cl₂) at 0° C. with 1.65 g ofN,O-dimethylhydroxylamine HCl, 1.7 g of triethylamine and 2.85 g ofhydroxybenzotriazole are added 5.37 g of1-[3-(dimethylamino)propyl]-3-ethylcarbodiimide hycrochloride. Themixture is stirred 17 h at room temperature. The mixture is concentratedtaken up in ethyl acetate (EtOAc) and washed with saturated sodiumbicarbonate, 1N HCl and brine, then dried (MgSO₄), filtered andconcentrated to give N-(R)-t-butoxycarbonyl-(p-phenylphenyl)-alanineN,O-dimethyl hydroxylamine aide.

To a 0° C. solution of N-(R)-t-butoxycarbonyl-(p-phenylphenyl)-alanineN,O-dimethyl hydroxylamine amide (5.2 g) in 250 ml of diethyl ether areadded 0.64 g of lithium aluminum hydride. The reaction is stirred for 30min. and quenched with aqueous potassium hydrogen sulfate. The mixtureis stirred for additional 5 min., poured onto 1N HCl, extracted (3x)with EtOAc, dried (MgSO₄), filtered, and concentrated to giveN-(R)4-t-butoxycarbonyl-(p-phenylphenyl)-alanine carboxaldehyde as acolorless oil.

To a 0° C. solution of N-(R)-t-butoxycarbonyl-(p-phenylphenyl)-alaninecarboxaldehyde (4.4 g) in 200 ml of CH₂ Cl₂ are added 10 g ofcarboethoxyethylidene phenyl phosphorane. The mixture is warmed to roomtemperature stirred for 1 h, washed with brine, dried (MgSO₄), filteredand concentrated. The residue is chromatographed on silica gel elutingwith (1:2) ether:hexane to giveN-t-butoxycarbonyl-(4R)-(p-phenylphenylmethyl)-4-amino-2-methyl-2-butenoicacid ethyl ester.

A solution ofN-t-butoxycarbonyl-(4R)-(p-phenylphenylmethyl)-4-amino-2-methyl-2-butenoicacid ethyl ester (4.2 g) in 400 ml of ethanol is suspended with 2.0 g of5% palladium on charcoal and then is hydrogenated at 50 psi for 6h. Thecatalyst is removed by filtration and the filtrate is concentrated togiveN-t-butoxycarbonyl(4S)-(p-phenylphenylmethyl)-4-amino-2-methylbutanoicacid ethyl ester as a 80:20 mixture of diastereomers.

To theN-t-butoxycarbonyl(4S)-(p-phenylphenylmethyl)-4-amino-2-methylbutanoicacid ethyl ester (4.2 g) in 40 ml of CH₂ Cl₂ at 0° C. is bubbled dryhydrogen chloride gas for 15 min. The mixture is stirred 2 h andconcentrated to give(4S)-(p-phenylphenylmethyl)-4-amino-2-methylbutanoic acid ethyl esterhydrochloride as a 80:20 mixture of diastereomers.

To a room temperature solution of the above amine salt (3.12 g) in 15 mlof CH₂ Cl₂ and 15 ml of pyridine are added 13.5 g of succinic anhydride.The mixture is stirred for 17 h, concentrated, dissolved in ethylacetate, washed with 1N HCl and brine, and dried (MgSO₄) to giveN-(3-carboxy-1-oxopropyl)-(4S)-(p-phenylphenylmethyl)-4-amino-2-methylbutanoicacid ethyl ester as a 80:20 mixture of diastereomers.

The above N-(3-carboxy-1-oxopropyl)-(4S)-(p-phenylphenylmethyl)-4-amino-2-methylbutanoic acid ethyl esterdiastereomeric mixture (3.9 g) and N,N-dimethylformamide-di-t-butylacetal (8.8 ml) are heated at 80° C. in 40 ml of toluene for 2 h. Themixture is poured onto ice-1N HCl, extracted with ether, chromatographedon silica gel eluting with (2:1) toluene:ethyl acetate to giveN-(3-carbo(t)butoxy-1-oxopropyl)-(4S)-(p-phenylphenylmethyl)-4-amino-2R-methylbutanoicacid ethyl ester as the more polar material and the corresponding (S,S)diastereomer as the less polar material.

EXAMPLE 2

To a solution ofN-(3-carboxy-1-oxopropyl)-(4S)-p-phenylphenylmethyl4-amino-(2R)-methylbutanoicacid ethyl ester (0.33 g) in 20 ml of (1:1)ethanol:tetrahydrofuran (THF)at room temperature are added 5 ml of 1N sodium hydroxide solution(NaOH) and stirred for 17 h. The mixture is concentrated, dissolved inwater and washed with ether. The aqueous layer is acidified with INhydrochloric acid (HCl), extracted 3x with ethyl acetate (EtOAc), driedover magnesium sulfate (MgSO₄), filtered and concentrated. The residueis triturated with ether to yieldN-(3-carboxy-l-oxopropyl)-(4S)-p-phenylphenylmethyl-4-amino-(2R)-methylbutanoicacid melting at 158°-164° C., [α]_(D) ²⁰ =-23.5° (methanol).

EXAMPLE 3

Following the procedures described in Examples 1 or 2, the followingcompounds are prepared:

N-(3-carboxy-1-oxopropyl)-(4S)-(p-phenylphenylmethyl)-4-amino-2S-methylbutanoicacid melting at 165°-167° C.;

N-(3-carboxy-1-oxopropyl)-(4S)-[p-(4-methylphenyl)phenylmethyl]-4-amino-2R-methylbutanoic acid melting at 165°-170° C., [α]_(D) ²⁰ =-18.4° (c=1,methanol);

N-(3-carboxy-1-oxypropyl)-(4R)-p-phenylphenylmethyl-4-amino-2S-methylbutanoicacid, melting at 145°-149° C.;

N-(3-carboxy-1-oxopropyl)-(4R)-p-phenylphenylmethyl-4-amino-(2R)-methylbutanoicacid, melting at 162°-165° C.;

N-(3-carboxy-1-oxopropyl)-4(S,R)-p-phenylphenylmethyl-4-amino-2(S,R)-methylbutanoic acid, melting at 165°-167° C.;

SodiumN-(3-carboxy-1-oxopropyl)-4(S,R)-p-phenylphenylmethyl-4-amino-2(S,R)-methylbutanoicacid ethyl ester, melting at 165°-167° C.;

SodiumN-(3-carboxy-1-oxopropyl)-(4R)-p-phenylphenylmethyl-4-amino-2S-methylbutanoicacid ethyl ester, melting at 117°-120° C.;

N-(3-ethoxycarbonyl-1-oxopropyl)-(4S)-(p-phenylphenylmethyl)-4-amino-2R-methylbutanoicacid, melting at 178°-190° C.;

N-(2-carboxy-1-oxoethyl)-(4S)-p-phenylphenylmethyl-4-amino-2(S,R)-methylbutanoicacid, melting at 160°-161° C.;

N-(5-carboxy-1-oxopentyl)-(4S)-p-phenylphenylmethyl-4-amino-2R-methylbutanoicacid, melting at 124°-127° C.;

SodiumN-(3-carboxy-1-oxopropyl)-4(S,R)-p-phenylphenylmethyl-4-amino-2(S,R)-methoxybutanoicacid, melting at 180°-185° C.;

SodiumN-(3-carboxy-1-oxopropyl)-4(S,R)-p-phenylphenylmethyl-4-amino-2(S,R)-methoxybutanoicacid indanyl ester, melting at 134°-136° C.;

N-(3-carboxy-1-oxopropyl)-(4S)-p-phenylphenylmethyl-4-amino-butanoicacid, melting at 163°-166° C.;

N-(3-carboxy-3-hydroxy-1-oxopropyl)-(4S)-p-phenylphenylmethyl-4-amino-2R-methylbutanoicacid, melting at 156°-170° C.

EXAMPLE 4

Following the procedures described in example 1 except substitutingglutaric anhydride for succinic anhydride, the following compounds areprepared:

N-(4-carboxy-1-oxobutyl)-(4S)-p-phenylphenylmethyl-4-amino-2R-methylbutanoic acid, melting at 152°-155° C. Sodium N-(4-carboxy- 1-oxobutyl)-(4S)-p-phenylphenylmethyl-4-amino-2R-methylbutanoic acidethyl ester, melting at 68°-72° C.

EXAMPLE 5

Following the procedures described in example 1 except substitutingcarbobutoxyethylidene phenyl phosphorane for carboethoxyethylidenephenyl phosphorane, the following compound is prepared:

SodiumN-(3-carboxy-1-oxopropyl)-(4S)-p-phenylphenylmethyl-4-amino-2R-methylbutanoicacid n-butyl ester, melting at 155°-165° C.

EXAMPLE 6

To a room temperature solution ofN-t-butoxycarbonyl-(4R)-p-phenylphenylmethyl-4-amino-2-methyl-2-butenoicacid ethyl ester (0.50 g) in 2 ml ethanol and 4 ml THF are added 2.0 mlof 1N NaOH. The reaction is stirred until the disappearance of startingmaterial monitored by thin layer chromatography. The mixture isconcentrated, dissolved in sodium bicarbonate and washed with ether. Theaqueous layer is acidified with 3N HCl and extracted (3x) with ethylacetate. The organic extracts are washed with brine, dried (MgSO₄),filtered and concentrated to giveN-t-butoxycarbonyl-(4R)-p-phenylphenylmethyl-4-amino-2-methyl-2-butenoicacid.

To a room temperature solution ofN-t-butoxycarbonyl-(4R)-p-phenylphenylmethyl-4-amino-2-methyl-2-butenoic acid (0.30 g) in 10 ml of CH2Cl₂ are added 0.123 g ofdimethyl aminopyridine, 0.203 g of 5-indanol and 0.387 g of1-[3-(dimethylamino)propyl]-3-ethylcarbodiimide hydrochloride. Themixture is stirred overnight, and then is concentrated and taken up inethyl acetate. The organics are washed with saturated sodium bicarbonate(2x), 1N HCl (2x) and brine (2x), dried (MgSO₄), filtered, concentratedand chromatographed on silica gel eluting with (1:4) ethylacetate:hexane to giveN-t-butoxycarbonyl-(4R)-p-phenylphenylmethyl-4-amino-2-methyl-2-butenoicacid indanyl ester. This material is convened to sodiumN-(3-carboxy-1-oxopropyl)-(4S)-p-phenylphenylmethyl-4-amino-2R-methylbutanoicacid indanyl ester melting at 60°-65° C. according to the proceduresdescribed in example 1.

EXAMPLE 7

To a solution of (4S)-p-phenylphenylmethyl-4-amino-2-methylbutanoic acidethyl ester hydrochloride (0.84 g) in 10 ml of methylene chloride areadded 0.58 g d adipic acid mono methyl ester, 0.293 g of triethylamine,0.49 g of hydroxybenzotriazole and 0.928 g of1-[3-(dimethylamino)propyl]-3-ethylcarbodiimide hydrochloride. Thereaction is stirred at room temperature overnight. The mixture isconcentrated and the residue is taken up in ethyl acetate. The organicsare washed with sodium bicarbonate, 1N HCl, brine, dried (MgSO₄),filtered and evaporated. The residue is chromatographed on silica geleluting with (1:2) ethyl acetate:hexane to give the more polardiastereomerN-(5-carbomethoxy-1-oxopentyl)-(4S)-p-phenylphenylmethyl-4-amino-2R-methylbutanoicacid ethyl ester. The less polar (S,S) diastereomer is also isolated.

To a solution ofN-(5-carbomethoxy-1-oxopentyl)-(4S)-p-phenylphenylmethyl-4-amino-2R-methylbutanoicacid ethyl ester (0.58 g) in 10 ml of THF and 10 ml of ethanol are added4.0 ml or 1N NaOH. The reaction is stirred overnight. The mixture isconcentrated taken up in water and washed with ether (2x). The aqueouslayer is acidified with 2N HCl and extracted with ethyl acetate (2x).The organics am dried (MgSO₄), filtered, concentrated and recrystallizedfrom methylene chloride-ether to giveN-(5-carboxy-1-oxopentyl)-(4S)-p-phenylphenylmethyl-4-amino-2R-methylbutanoicacid, melting at 124°-127° C.

EXAMPLE 8

Preparation of 1,000 capsules each containing 50 mg of the activeingredient, as follows:

    ______________________________________                                        N-(3-carboxy-1-oxopropyl)-(4S)-(p-phenylphenyl-                                                           50.00 g                                           methyl)-4-amino-2R-methylbutanoic acid ethyl ester                            sodium salt                                                                   Lactose                     187.00 g                                          Modified starch             80.00 g                                           Magnesium stearate          3.00 g                                            ______________________________________                                    

Procedure: All the powders are passed through a screen with openings of0.6 mm. The drug substance is placed in a suitable mixer and mixed firstwith the magnesium stearate, then with the lactose and starch untilhomogenous. No. 2 hard gelatin capsules am filled with 300 mg of saidmixture each, using a capsule filling machine.

Analogously capsules are prepared, containing about 10-100 mg of theother compounds disclosed and exemplified herein, e.g. the compounds ofexamples 1-5.

What is claimed is:
 1. A compound of formula I ##STR18## wherein COX andCOX' independently represent carboxyl or carboxyl derivatized in form ofa pharmaceutically acceptable ester or amide; R₁ represents hydrogen,lower alkyl, C₃ -C₇ -cycloalkyl-lower alkyl, aryl-lower alkyl,biaryl-lower alkyl, lower alkoxy, aryl-lower alkoxy, aryloxy, N-loweralkylamino, N,N-di-lower alkylamino, N-aryl-lower alkylamino,N,N-di-aryl-lower alkylamino, N-arylamino, N-N-diarylamino, loweralkanoylamino, aryl-lower alkanoylamino or aroylamino; R₂ representshydrogen, hydroxy, lower alkoxy, lower alkyl, aryl-lower alkyl, C₃ -C₇-cycloalkyl-lower alkyl, amino-lower alkyl, hydroxy-lower alkyl, loweralkylthio-lower alkyl, lower alkoxy-lower alkyl, aryl-loweralkylthio-lower alkyl or aryl-lower alkoxy-lower alkyl; biarylrepresents phenyl substituted by carbocyclic or heterocyclic aryl; Arepresents a direct bond, lower alkylene, phenylene or cyclohexylene; mrepresents 1 or zero, provided that m represents 1 when A is a directbond; carbocyclic aryl within the above definitions represents phenyloptionally substituted by lower alkyl, lower alkoxy, halogen, hydroxy,cyano, lower alkanoyloxy or trifluoromethyl; heterocyclic arylrepresents thienyl or furanyl optionally substituted by lower alkyl; ora pharmaceutically acceptable salt thereof.
 2. A compound according toclaim 1 of formula Ia ##STR19## wherein COOR and COOR' independentlyrepresent carboxyl or carboxyl derivatized in form of a pharmaceuticallyacceptable ester, R₁ represents hydrogen, lower alkyl, lower alkoxy,N-lower alkylamino, lower alkanoylamino, aryl-lower alkyl, aryl-loweralkoxy, aryloxy, N-arylamino or aroylamino wherein aryl in each caserepresents phenyl optionally substituted by lower alkyl, lower alkoxy,halogen, hydroxy, cyano, acyloxy or trifluoromethyl; or aryl representsthienyl or furanyl optionally substituted by lower alkyl; R₂ representshydrogen, hydroxy, lower alkyl or aryl-lower alkyl wherein aryl has themeaning given above, R₃ represents phenyl, or phenyl substituted bylower alkyl, lower alkoxy, halogen, cyano, lower alkanoyloxy ortrifluoromethyl; or R₃ represents thienyl or furanyl optionallysubstituted by lower alkyl; A represents a direct bond, lower alkylene.,1,4-phenylene or 1,4-cyclohexylene; m represents 1 or zero provided thatm represents 1 when A is a direct bond; or a pharmaceutically acceptablesalt thereof.
 3. A compound according to claim 2 wherein R₃ is locatedin the para position.
 4. A compound according to claim 1 of formula Ib##STR20## wherein COOR and COOR' independently represent carboxyl orcarboxyl derivatized in form of a pharmaceutically acceptable ester, R₁is hydrogen, lower alkyl, lower alkoxy or aryl-lower alkyl wherein arylrepresents phenyl optionally substituted by lower alkyl, lower alkoxy,halogen, hydroxy, cyano, acyloxy or trifluoromethyl; R₂ representshydrogen, hydroxy or lower alkoxy; R₄ and R₅ independently representhydrogen, lower alkyl, hydroxy, lower alkoxy, halogen, cyano ortrifluoromethyl; A represents lower alkylene; m represents 1 or zero; ora pharmaceutical acceptable salt thereof.
 5. A compound according toclaim 4 of formula Ic ##STR21## wherein COOR and COOR' independentlyrepresent carboxyl or carboxyl derivatized in form of a pharmaceuticallyacceptable ester, R₁ is lower alkyl or lower alkoxy; R₄ representshydrogen, lower alkyl, lower alkoxy, halogen, or trifluoromethyl; nrepresents an integer 1 through 6; or a pharmaceutical acceptable saltthereof.
 6. A compound according to claim 5 of formula Ic wherein COORand COOR' independently represent carboxyl, C₁ -C₂₀ -alkoxycarbonyl,(carbocyclic or heterocyclic aryl)-lower alkoxycarbonyl, (di-loweralkylamino, N-lower alkylpiperazino, morpholino, pyrrolidino, piperidinoor perhydrazepino)-C₂ to C₄ -alkoxycarbonyl,dihydroxypropyloxycarbonylprotected in form of a ketal, 5-indanyloxycarbonyl,3-phthalidoxycarbonyl, bicycloalkoxycarbonyl-lower alkoxycarbonyl,α-(lower alkoxycarbonyl or di-lower alkylaminocarbonyl)-loweralkoxycarbonyl, 1-(lower alkoxycarbonyloxy)-lower alkoxycarbonyl or1-(lower alkanoyloxy)-lower alkoxycarbonyl; or a pharmaceuticallyacceptable salt thereof.
 7. A compound according to claim 1 of formulaId ##STR22## wherein R₁ is lower alkyl; n is an integer 1 through 4; ora pharmaceutically acceptable mono- or di-ester derivative thereof inwhich one or two of the acidic hydroxy groups of the carboxyl functionalgroups are esterified in form of a mono- or di-pharmaceuticallyacceptable ester, or a pharmaceutically acceptable salt thereof; or anoptical antipode thereof.
 8. A neutral endopeptidase inhibitingpharmaceutical composition comprising an effective neutral endopeptidaseinhibiting amount of a compound of claim 1 in combination with one ormore pharmaceutically acceptable carriers.
 9. A method of treatingcardiovascular disorders which comprises administering to a mammal inneed of such treatment an effective neutral endopeptidase inhibitingamount of a compound of claim 1 in combination with one or morepharmaceutically acceptable carriers.
 10. A compound according to claim5 beingN-(3-carboxy-1-oxopropyl)-4-(p-phenylphenylmethyl)-4-amino-2-methoxybutanoicacid or a pharmaceutically acceptable salt thereof.